Abstract Understanding the function of lung progenitor cells is a critical to improve our fundamental understanding of lung development, but is also critical to design strategies aimed at improving lung regeneration or repair following injury. Recent evidence has demonstrated that significant functional and gene expression species- specific differences exist when comparing the developing human and mouse lung, suggesting that our fundamental understanding of human lung development is incomplete. This proposal will build on novel methods that allow us to isolate and propagate epithelial progenitor cells from developing human lungs in vitro, and novel methods to induce human lung epithelial progenitor cells from iPSCs in vitro. iPSC-derived lung progenitors are capable of long-term engraftment into the injured mouse airway where they differentiated multiple cell types within the adult murine lung. Through these studies, we have collectively defined an in vitro niche comprised of a minimal set of biochemical cues along with a physical environment (extracellular matrix) that supports lung epithelial progenitor cell growth in vitro. However, how niche factors functions to support lung epithelial progenitor maintenance and/or differentiation is unclear. This proposal will pursue aims that are designed to understand how specific niche factors mechanistically support epithelial progenitors in the developing human lung, and to interrogate the mechanisms by which human lung epithelial progenitor cells undergo cell fate specification.